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New Directions in Sickle Cell Therapy in the Genome Era

Conference Talk Summaries

The Pathophysiology of Sickle Cell Disease: State of the Art
Martin Steinberg, M.D.

Dr. Steinberg presented an overview of current knowledge about the pathophysiology of sickle cell disease (SCD), highlighting polymerization, membrane damage, inflammation, perfusion-reperfusion injury, oxidative damage, and altered nitric oxide biology as important aspects of the disease process. He discussed the clinical features of SCD as falling under the general rubrics of vasoocclusion and hemolysis. He suggested a "new" view of SCD pathophysiology would include that: the hemoglobin S mutation is necessary but insufficient to account for disease pathophysiology; many other modifier genes determine disease phenotype; some of these act "uniformly," influencing more than one sub-phenotype, while others are phenotype-specific; and these genes and their variants determine disease severity by modulating the effects of the hemoglobin S mutation and interacting with each other and the environment.

Therapeutics for Sickle Cell Disease: State of the Art
Elliott Vichinsky, M.D

Dr. Vichinsky gave an overview of current and promising therapeutic agents in SCD. He noted a trend towards loss of adult-focused clinical research in SCD, leaving an almost sole focus on pediatric aspects of the disease and suggested that this trend needs to be reversed. He also noted that while some recommended interventions, such as penicillin prophylaxis, have proven clinically important and have found wide adoption, some, such as use of hydroxyurea, are not implemented in the care of many patients. Other current impediments that he discussed included lack of autopsy/histology data, pharmaceutical companies viewing SCD as lacking sufficient marketing potential to warrant investment, continuing loss of SCD researchers, and lack of structures to address long-term care needs. Dr. Vichinsky thought that unrelated bone marrow transplant is very promising, especially when extended haplotype matching is utilized, and felt that cord blood transplantation is also promising. He cited a need for prospective studies of various interventions, e.g., steroids, surfactant, pheresis for iron overload, and alloimmunization prevention. He also recommended further consideration of such interventions as chemotherapeutic agents, anti-oxidative therapies, nitric oxide, decitabine, red blood cell rehydration, arginine, and PCA-2 inhibition.

Therapeutic Implications of Phenotypic Diversity
Orah Platt, M.D.

Dr. Platt spoke about the phenotypic diversity seen in SCD and the implications of this diversity for therapeutics and for research. She noted that the degree of phenotypic diversity seen in such work as the Cooperative Study of Sickle Cell Disease would not have been predicted from knowledge of the underlying molecular lesion alone, but that it was in accord with the diversity seen in the red blood cells themselves (due to varying age and exposure to oxidants, macrophages, viruses, dehydration, etc.). She described SCD as operating in some aspects as a Mendelian disorder, in others as a "sort of Mendelian" disorder, and in still others as a complex disease. Dr. Platt suggested that some therapies (such as bone marrow transplantation or gene transfer) might focus on the Mendelian character of SCD, while others (such as hemoglobin switching or chemical genomics) might aim at the "sort of Mendelian" aspects, and still other therapies (such as those that affect inflammation or adhesion) must approach SCD as a complex disorder. She also discussed the use in research of intermediate phenotypes, unrelated and related subjects with SCD, and related subjects without SCD to understand phenotypic diversity more completely. She stressed both the difficulty inherent in phenotyping those with SCD fully and the importance of doing so. Dr. Platt closed by calling for a "Sickle Cell Phenome Project" that would support the development of experts in clinical medicine, clinical investigation, and cultural aspects of disease, as well as technology-savvy translational researchers with expertise in genomics, expression studies, imaging, etc. Such a project would also support clinical-technology based phenotyping centers that included imaging, physiologic metrics, etc. and centralized phenotyping laboratories that offered biochemistry, hematology, and repository services, as well as informatics and genomics capabilities in a setting that catalyzes cooperative approaches. Through public education and research on overcoming barriers to research participation, this project might also support a national focus on recruitment to participation in research. Finally, the project could help integrate phenomics and genomics into such major clinical trials as the Cooperative Study of Sickle Cell Disease and the Stroke Prevention Trial in Sickle Cell Anemia.

Hemoglobin Switching
George Stamatoyannopoulos, M.D., Dr.Sci.

Dr. Stamatoyannopoulos traced the development of the field of hemoglobin switching in SCD over the past half century, reviewed its current state and outlined promising areas for future research. He noted that, in 2003: efforts to develop pharmacologic induction of fetal hemoglobin demonstrate very slow progress in the discovery of new inducers; follow-up to discovery is absent because it is almost impossible to bring discoveries to the clinic; and a critical mass of SCD investigators no longer exists. Dr. Stamatoyannopoulos felt the paucity of investigators was partly due to the field having become "unfriendly" to young researchers. He characterized SCD clinical trials as having become very conservative, lacking innovation and coordination. He then reviewed in depth what is known about the activation, control and expression of ?-globin genes and current strategies for increasing such knowledge.

Gene Transfer
Michel Sadelain, M.D., Ph.D., Memorial Sloan-Kettering Cancer Center

Dr. Sadelain provided an overview of current and projected gene transfer efforts. He characterized the aim of gene transfer for SCD as to create a long-lasting effect on erythropoiesis. He noted that criteria for effective globin vectors include: being erythroid specific; stage specific differentiation; position independent but copy-number dependent; etc. In terms of "next questions" to tackle in this area, he highlighted stable lentiviral packaging cell lines, large scale vector production, evaluation of lentiviral globin vectors in human stem and erythroid cells, optimization of conditioning regimens for autologous transplantation with gene transfer, and optimization of conditions for in vivo selection (enrichment of gene-modified cells). He also discussed which types of vectors appear particularly promising for further development and use. Dr. Sadelain noted that, because in SCD one needs to affect more than 80% of cells, in vivo selection is likely to be necessary.

Small Molecule/Chemical Genomics Approaches
John Haley, Ph.D.

Dr. Haley reviewed pharmacological approaches to SCD and the use of chemical genomics to further understanding of the biology of SCD and to develop new therapeutics for the disorder. He noted that pharmacological agents are usually designed to prevent polymerization through inducing fetal hemoglobin formation, or to combat vasoocclusion through increasing peripheral vasodilatation. Dr. Haley discussed modulators of nitric oxide synthesis in management of SCD. He suggested that combining compounds that induce fetal hemoglobin at sub-optimal, nontoxic plasma concentrations with agents that increase peripheral blood flow (e.g., nitrites) should be investigated. He considered how genomics-based approaches, such as high throughput screening to develop compounds that increase ?-globin transcription and microarrays to explore histone deactylase inhibitor associated gene expression changes, might play a role in SCD. He described lead candidate selection as the major current bottleneck in developing new therapeutics for SCD.

Historical, Cultural, and Social Context of Clinical Research in Sickle Cell Disease
Vanessa Northington Gamble, M.D., Ph.D.

Dr. Gamble depicted SCD as a "racial disease" and explored the relationship between SCD and the construction of race in the U.S. She discussed how historical analysis demonstrates that definitions of race have been fluid, inconsistent, and often influenced by social and political factors. She described 1969-1973 as the period during which SCD emerged from obscurity to visibility and the years afterward as the period during which it went from visibility to controversy. Dr. Gamble discussed SCD's relationship to ethnic and racial disparities in health, suggesting that social, cultural, and political factors have influenced the history of sickle cell disease and that an understanding of these factors must inform contemporary policy and programs. She closed by detailing a number of opportunities and/or challenges for SCD research, including: analyzing the social and cultural context of SCD within a global context; developing screening and clinical policies and guidelines that take the changing demography of the U.S. into account; overcoming the dilemma of difference and advancing trustworthiness; establishing visibility and support for SCD in the new context of racial and ethnic disparities in health; comprehending the attitudes of members of minority groups toward sickle cell disease and genetics; developing minority investigators in the areas of ethical, legal, and social issues; creating culturally competent educational programs; promoting community partnership and involvement; clarifying the role of social factors in the health outcomes of people with sickle cell anemia; understanding the experience of people with sickle cell disease; and developing strategies to diversify participants in clinical trials.

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Last Reviewed: November 22, 2013